Expression of ABCG5 and ABCG8 Is Required for Regulation of Biliary Cholesterol Secretion

Abstract

The major pathway for elimination of cholesterol in mammals is via secretion into bile. Biliary cholesterol secretion is mediated by the ATP-binding cassette (ABC) transporters ABCG5 (G5) and ABCG8 (G8) and is stimulated by cholesterol and by the non-cholesterol steroids cholate and diosgenin. To define the relationship between G5G8 expression and biliary cholesterol secretion, we measured G5 and G8 mRNA levels and biliary cholesterol concentrations in genetically manipulated mice expressing 0, 1, 2, 5, 10, or 16 copies of the two genes. Biliary cholesterol levels varied directly with G5G8 copy number and hepatic mRNA levels over a >16-fold range. Thus neither delivery of cholesterol to the transporter nor levels of cholesterol acceptors in bile were limiting under these conditions. In wild-type mice, cholate and diosgenin both increased biliary cholesterol concentrations 2-3-fold. The increase in biliary cholesterol content was dependent on expression of G5 and G8; neither steroid increased biliary cholesterol levels in G5G8 ؊/؊ mice. Cholate treatment was associated with a farnesoid X receptor (FXR)-dependent increase in hepatic mRNA and protein levels of G5 and G8. In contrast to cholate, diosgenin treatment did not affect G5G8 expression. Diosgenin increased the expression of several pregnane X receptor (PXR) target genes and the choleretic effect of diosgenin was reduced by ϳ70% in PXR knock-out mice. Thus G5 and G8 are required to modulate biliary cholesterol secretion in response to cholate and diosgenin, but the choleretic effects of these two steroids are mediated by different mechanisms requiring FXR and PXR, respectively.

Benefit of farnesoid X receptor inhibition in obstructive cholestasis

“…Loss of FXR therefore would be expected to reduce bile formation and prevent hydrostatic rupture of the canals of Herring after BDL (14). Biliary cholesterol secretion is mediated by the ABC transporters ABCG5 and ABCG8 and is a major pathway for cholesterol elimination (20). We found that ABCG8 expression was repressed in WT mice after BDL but induced in FXRKO mice, suggesting that FXRKO mice may have greater capacity to excrete cholesterol into bile.…”

Protein Kinase A Suppresses Sterol Regulatory Element-binding Protein-1C Expression via Phosphorylation of Liver X Receptor in the Liver

“…It is also possible that phosphorylation states of these critical sites control other potential phosphorylation sites. LXR/RXR also transactivate other genes such as the ABCA1 (36) and the ABCG family (37,38). The LXR␣-induced activity of the ABCA1 promoter containing LXRE was also repressed by PKA similarly to the SREBP-1c promoter.…”

Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols

“…Sterolins are critically involved in regulating the wholebody retention of noncholesterol plant sterols, and that these proteins are also key to secreting cholesterol into the biliary lumen (and likely the intestinal lumen) [30,32,35,46,[64][65][66]. The genetic disease of sitosterolemia attests to their role in keeping noncholesterol sterols (plant sterols as well as shellfish sterols, etc.)…”